Protein misfolding and aggregation comprise the underlying common pathological mechanism of many neurodegenerative disorders. In the case of tauopathies, a group of neurodegenerative diseases which include Alzheimer's disease (AD) and frontotemporal dementias, the hyperphosphorylation and aggregation of the microtubule (MT)-associated protein tau is believed to have pathological consequences via toxic gain and/or loss of functions. Previous studies from our laboratories have demonstrated that administration of low once- weekly doses of the brain-penetrant MT-stabilizing agent, epothilone D (epoD), to tau transgenic (Tg) mice resulted in improved axonal transport, reduced axonal dystrophy, enhanced cognitive performance and decreased neuronal pathology. These results thus suggest that compensation for the loss of tau MT-stabilizing function may be a viable therapeutic strategy for the treatment of tauopathies. However, epoD is the only example of a brain-penetrant MT-stabilizing agent that to date has undergone in vivo efficacy studies in tau Tg animal models. As a result, the development and evaluation of additional CNS-active MT-stabilizing agents is clearly desirable so as to identify alternative and potentially improved clinical candidates. Towards this end, we have recently discovered that dictyostatin, a potent naturally occurring MT-stabilizing agent that is structurally unrelated to the epothilones, exhibit excellent brain penetration and long-lasting pharmacodynamic effects. These findings clearly suggest that dictyostatin may be a viable drug candidate for the treatment of tauopathies. Thus, the objectives of the proposed research plan are to synthesize quantities of dictyostatin (Aim 1) that would be sufficient to fully characterize both pharmacokinetics and pharmacodynamics of this natural product, followed by tolerability/safety studies in normal mice (Aim 2). The results o Aim 2 will guide the dose amount and dosing frequency for studies in an established tau Tg mouse model, in which the efficacy of dictyostatin will be directly compared to epoD (Aim 3). In addition, since dictyostatin will become a public domain compound in April, 2014, thereby hampering future development and commercialization, we will design, synthesize and evaluate a focused series of patentable dictyostatin prodrugs that are designed to release the active natural product in plasma upon administration (Aim 4). If successful, the proposed research plan will: (a) validate dictyostatin as a drug candidate for the treatment of tauopathies and (b) identiy one or more patentable prodrugs of the natural product. These studies will form the basis of a subsequent drug-development plan (U01) in which the objective will be to advance a preferred dictyostatin prodrug to the point of filing of an IND.